HIV-1 based lentiviral vectors are becoming an increasingly attractive means of integrating transgenes into target cells. Vectors are in or enterning clinical trials for a diverse group of ailments, including genetic disease, AIDS and cancer. Rimedion and its research partner, Indiana University School of Medicine proposes to develop a novel lentiviral vector for the treatment of Fanconi anemia. While the vector construct will be derived from HIV-1 based lentiviral system, the vector will be pseudotyped with a proprietary viral envelope derived from the human foamy virus. Specific Aim 1: Generate recombinant lentiviral constructs that encode the expression of the FANCA cDNA by the human phosphoglycerate kinase promoter or the elongation factor 1a promoter and test functional expression of the transgenes in murine Fanca -/- progenitors and human FANCA deficient lymphoblastoid cell lines. Specific Aim 2: Optimize production of a lentiviral vector pseudotyped with a proprietary PFV envelope using GMP complaint methodology. In this Phase I application, the clinical vector construct and optimized production methodology will finalized. In Phase II, Rimedion will generate vector and complete efficacy and toxicity data for inclusion in an IND filing. The work will lead to a Phase I clinical trial using the novel vector to transduce autologous peripheral blood stem cells from Fanconi anemia patients. As discussed in our application, the proof-of-principle has been well established that gene transfer can correct the hematologic defects of this disease, the efficiency of gene transfer using prior vector systems has been the major limitation to developing a commerical product. Rimedion believes the novel vector system described will provide a curative therapy for this genetic disease. PUBLIC HEALTH RELEVANCE: Gene therapy for Fanconi anemia has been successful in murine models but human cures have been limited by the low transduction efficiency of retroviral vectors. Rimedion will utilize a novel lentiviral vector combined with a proprietary foamy virus envelope to improve efficiency and decrease toxicity of gene transfer. Rimedion will optimize the vector and production methods in this application enabling a Phase I clinical trial.